The American Journal on Addictions, 18: 4852, 2009

Copyright
C
American Academy of Addiction Psychiatry
ISSN: 1055-0496 print / 1521-0391 online
DOI: 10.1080/10550490802544318
Olanzapine in Cocaine Dependence: A Double-Blind,
Placebo-Controlled Trial
Joseph D. Hamilton, MD,
1
Quang X. Nguyen, PhD,
2
Robert M. Gerber, MD,
2
Nancy B. Rubio, MD
2
1
Michael E. DeBakey VA Medical Center; VA South Central Mental Illness Research, Education, and Clinical Center; and
Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas
2
Michael E. DeBakey VA Medical Center and Menninger Department of Psychiatry and Behavioral Sciences, Baylor College
of Medicine, Houston, Texas
Preclinical and uncontrolled human studies have suggested
the possible efcacy of second-generation antipsychotics,
particularly olanzapine, in treating cocaine dependence. We
conducted a randomized, double-blind, placebo-controlled
trial in which 48 cocaine-dependent subjects received olan-
zapine or identical-appearing placebo for 16 weeks. The
primary outcome measure was the proportion of cocaine-
negative weekly urine screens during treatment. Secondary
measures included scores on a Craving Questionnaire, Ad-
diction Severity Index subscales, and extrapyramidal symptom
scales. Olanzapine and placebo did not differ on any outcome
measure. Both olanzapine and placebo subjects frequently
reported side effects, but no unexpected ones. We conclude
that olanzapine appears ineffective for cocaine dependence.
(Am J Addict 2009;18:4852)
INTRODUCTION
The high prevalence of cocaine abuse and dependence
has for many years prompted research into pharmacologic
interventions as a component of treatment. Because the
stimulation of the mesolimbic dopamine system plays a major
part in cocaines addictive effect, the dopamine receptor
blocking effects of antipsychotic drugs have made them of
interest as potential pharmacotherapy for cocaine dependence.
Earlier studies with rst-generation antipsychotics, particu-
larly upenthixol, in cocaine dependence produced equivocal
and inconsistent results;
1
indeed, one controlled study has
suggested that discontinuing typical antipsychotics might
Received February 21, 2006; revised March 23, 2006; accepted
June 26, 2008.
Dr. Hamilton is now Professor Emeritus at Baylor College of
Medicine.
Address correspondence to Dr. Hamilton, 4413 Betty St., Bellaire,
TX 77401.
improve cocaine craving, at least in patients with other major
mental disorders.
2
The advent of second-generation antipsychotics created
fresh hopes for efcacy in cocaine dependence because of
their atypical proles of action. In particular, olanzapine
showed promise in blocking cocaine self-administration in
some animal studies,
3,4
though other preclinical data were less
positive.
5
In human subjects, case reports
68
and uncontrolled
trials
9,10
of olanzapine were encouraging. However, the only
controlled study published to date has been a 12-week
trial showing no effect, or even a possible worsening, from
olanzapine treatment of cocaine dependence.
11
In view of the
conicting evidence, we conducted a randomized, double-
blind, placebo-controlled, parallel-group trial for 16 weeks
to determine whether olanzapine helped cocaine-dependent
patients.
METHODS
The subjects were 48 cocaine-dependent outpatients en-
rolled in the Substance Dependence Treatment Program
(SDTP) at our VA Medical Center. Inclusion criteria were
an age of at least 18 years; a diagnosis of cocaine dependence,
as determined by a clinician interview using a checklist of
DSM-IV criteria; and active use of cocaine within the past 30
days, as determined by urine testing or self-report. Exclusion
criteria were currently receiving antipsychotic medication;
current DSM-IV diagnosis of schizophrenia, schizoaffective
disorder, schizophreniform disorder, or delusional disorder;
current active psychotic symptoms (delusions, hallucinations,
or markedly disorganized speech); a history of bipolar disorder
(not due to cocaine) or major depressive disorder (not due to
cocaine) by DSM-IV criteria, established by medical record
review or by clinical interview at recruitment; hypersensitivity
to olanzapine; or serious unstable medical illness (including
serious renal disease, serious hepatic disease with liver
enzymes at more than three times the upper limits of normal,
48
myocardial infarction within the past 60 days or other serious
unstable cardiac disease, or history of seizures other than those
due to substance withdrawal). We paid subjects $20 per visit,
except for the initial screening visit to check for inclusion
and exclusion criteria. Subjects provided written informed
consent, and the Institutional Review Board of Baylor College
of Medicine approved the study.
Although we initially intended to stratify subjects into
two groups (those already enrolled in SDTP at recruitment,
and those who rst enrolled in SDTP at recruitment) before
randomization, all subjects recruited were in fact already
enrolled in SDTP before recruitment. We randomized subjects
to receive in double-blind fashion either olanzapine or placebo
(1:1 ratio) orally for 16 weeks, during which they attended
weekly study visits. When a subject enrolled in the study,
a support staff member not involved with the treatment of
subjects obtained the randomization assignment by opening
a sealed opaque envelope and conveyed the assignment to
a research pharmacist, who dispensed the study medication
in coded containers. The starting dose of study medication
was 2.5 mg olanzapine per day (or equivalent identical-
appearing placebo). The dose could be titrated up to a
maximum total olanzapine daily dose of 20 mg (or equivalent
identical-appearing placebo) at the investigators discretion
according to clinical response (eg, subjects report of continued
craving for cocaine) and side effect tolerability. The minimum
titration increment was 2.5 mg; allowed titration intervals
were every week for the rst three weeks and then every
two weeks thereafter. The research pharmacist dispensed the
medication to all subjects at these same intervals. Subjects
were instructed to return their pill bottle at each visit in
which medication was dispensed, so that a pill count could
be done to check adherence to the study medication regimen.
Medication was stopped at visit 16, and subjects received
a follow-up evaluation (visit 17) four weeks later. Thus,
subjects came for a total of 17 visits over 20 weeks. During
the study, all subjects participated in the usual treatment
program of the SDTP, consisting of a variety of psychother-
apeutic and educational groups, strong encouragement to
attend 12-step meetings, family interventions and social case
work as indicated, and individual addiction counseling and
case management. Counseling approaches included 12-step,
medical education, relapse prevention, and peer support.
Subjects attended SDTP treatment from one to ve days per
week, depending upon their treatment stage and treatment
response. Any concomitant medications were allowed for
study subjects as indicated, except for antipsychotics and
antidepressants.
At visit 1, subjects received a physical examination of vital
signs and weight (repeated at every visit), a checklist of cocaine
withdrawal symptoms (as dened in DSM-IV), a serum chem-
istry panel (electrolytes, glucose, blood urea nitrogen [BUN],
creatinine, total protein, albumin, phosphorus, total bilirubin,
uric acid, alkaline phosphatase, aspartate aminotransferase,
alanine aminotransferase, and lactate dehydrogenase; repeated
at visits 6 and 17), a serum pregnancy test (for women of
child-bearing potential), complete blood count (repeated at
visits 6 and 17), electrocardiogram (repeated at visit 17), and
urine drug test for cocaine (repeated at every visit). The urine
test for cocaine was an enzyme immunoassay (Synchron LX
Systems) for the cocaine metabolite benzoylecgonine, with a
positive test threshold of 300 ng/ml. To measure changes in
craving and behaviors associated with cocaine dependence,
we administered the Craving Questionnaire (visits 14, 6, 8,
10, 12, 14, 16, and 17), which has shown good psychometric
properties and validity,
12
and the Addiction Severity Index
(ASI; visits 1, 8, 16, and 17), which has been extensively
validated in VA and non-VA substance-abusing populations.
13
We administered a general side effects checklist at visits 24, 6,
8, 10, 12, 14, 16, and 17. To specically detect extrapyramidal
side effects, at visits 1, 4, 8, 12, 16, and 17 we administered
the Abnormal Involuntary Movement Scale (AIMS),
14
the
Simpson-Angus Scale,
15
and the Barnes Akathisia Scale,
16
all of which have been widely used and well validated in
antipsychotic drug studies.
We computed descriptive statistics for the demographic and
dependent variables. Chi-square analyses (test for homogene-
ity of proportions) and one-way analyses of variance (ANOVA)
examined potential differences between the olanzapine and
placebo groups regarding demographic characteristics, urine
drug screen status, and the dependent measures at baseline.
As our primary outcome measure, we conducted a one-way
ANOVA to compare the mean proportion of negative urine
drug screens between the two groups during the treatment
period of the study (visits 116). We also compared the
proportion of subjects remaining totally abstinent fromcocaine
(ie, with all urine drug screens negative) during the 16-
week treatment period in the olanzapine versus the placebo
group, using a chi-square test. We performed repeated-
measures ANOVAs to examine the effect of the treatment
group (olanzapine versus placebo) over time (baseline, end
of treatment, follow-up) on the Craving Questionnaire, the
Barnes Akathisia Scale, the Simpson-Angus Scale, the AIMS,
and the ASI subscales. We tabulated descriptive statistics
about side effects. To address attrition, we conducted chi-
square analyses and one-way ANOVAs to examine potential
differences between participants who came for at least eight
visits versus those who had fewer than eight visits, with
regard to demographic variables, group assignment, and the
dependent measures at baseline.
RESULTS
Baseline Characteristics
All 48 subjects were male veterans, with a mean age of
45.8 years (SD 6.8; range 3360); 41 (85.4%) were black
and 7 (14.6%) were white. In the 30 days before study
entry, the subjects had used cocaine for a mean of 11.28
(SD 7.23) days and had spent a mean of $357 (SD $450)
on drugs. Their reported routes of cocaine administration
were 73.9% smoking, 10.9% nasal, 6.5% IV, 6.5% non-IV
injection, and 2.2% oral. Other substances used during the 30
Hamilton et al. JanuaryFebruary 2009 49
TABLE 1. Scores of subjects at baseline, end of treatment, and follow-up
Baseline (week 1) End of treatment (week 16) Follow-up (week 20)
Variable Mean (SD) N

Mean (SD) N

Mean (SD) N

Craving Questionnaire 4.29 (2.29) 48 1.21 (1.51) 19 1.63 (2.00) 18

Barnes Akathisia scale 0.17 (0.35) 47 0.14 (0.30) 19 0.08 (0.30) 18
Simpson-Angus scale 0.03 (0.08) 47 0.02 (0.05) 19 0.02 (0.07) 18
AIMS 0.77 (1.28) 47 0.42 (0.77) 19 0.28 (0.75) 18
ASI medical 0.41 (0.35) 45 0.33 (0.35) 17 0.31 (0.40) 16
ASI employment 0.68 (0.22) 46 0.51 (0.21) 17 0.54 (0.24) 16
ASI alcohol 0.30 (0.22) 46 0.06 (0.07) 17 0.05 (0.08) 16
ASI drug 0.24 (0.09) 46 0.10 (0.11) 17 0.12 (0.11) 16
ASI legal 0.08 (0.13) 46 0.08 (0.16) 17 0.03 (0.09) 16
ASI family 0.25 (0.20) 46 0.09 (0.12) 17 0.06 (0.10) 16
ASI psychiatric 0.28 (0.22) 45 0.17 (0.26) 17 0.09 (0.19) 16

N varies because of missing data.

days before entry included alcohol (85.1%), heroin (6.4%),
methadone (10.6%), other opioids (8.5%), sedative-hypnotics
(14.9%), and cannabis (25.5%). No subjects reported using
amphetamines, hallucinogens, or inhalants; 87.2% reported
using more than one substance per day. Comorbid diagnoses
in subjects clinical records included depression not otherwise
specied (2.1%), dysthymic disorder (2.1%), posttraumatic
stress disorder (2.1%), obsessive-compulsive disorder (4.2%),
and bereavement (2.1%). Table 1 shows subjects means,
standard deviations, and ranges for the Craving Questionnaire,
the Barnes Akathisia Scale, the Simpson-Angus Scale, the
AIMS, and the seven subscales of the ASI at baseline.
There were 23 subjects randomized to olanzapine and
25 to placebo. We conducted analyses to examine whether
the randomization of subjects to the olanzapine and placebo
groups produced any signicant differences at baseline on
the demographic variables and the dependent measures. A
one-way ANOVA revealed no signicant difference between
the two groups in age (F(1,46) = 1.123, p = 0.295), and
chi-square revealed no signicant difference in race/ethnicity
(
2
(1, N = 48) = 0.014, p = 0.905). A series of one-way
ANOVAs similarly revealed no signicant differences between
the two groups regarding scores on the Craving Questionnaire
(F(1,46) = 1.097, p = 0.300), the Barnes Akathisia Scale
(F(1,45) = 0.296, p = 0.589), the Simpson-Angus Scale
(F(1,45) = 2.144, p = 0.150), the AIMS (F(1,45) = 0.099,
p = 0.755), the ASI medical subscale (F(1,43) = 0.098,
p = 0.756), the ASI employment subscale (F(1,44) = 0.004,
p = 0.950), the ASI alcohol subscale (F(1,44) = 0.847, p =
0.362), the ASI drug subscale (F(1,44) = 0.701, p = 0.407),
the ASI legal subscale (F(1,44) =0.469, p =0.497), the ASI
family subscale (F(1,44) = 0.337, p = 0.564), and the ASI
psychiatric subscale (F(1,43) = 0.026, p = 0.872). Finally, a
chi-square analysis showed no signicant difference in urine
drug screen result (ie, negative or positive for cocaine) between
the two groups at baseline (
2
(1, N = 45) = 1.213, p =
0.271).
Urine Cocaine Test Results
We calculated the proportion of negative urine cocaine tests
for each subject during the treatment period and then con-
ducted a one-way ANOVA to compare the mean proportions
between the two groups. The mean proportions of negative
tests over the entire treatment period for the olanzapine group
(0.79, SD 0.29, N = 23) and the placebo group (0.66, SD
0.35, N = 25) showed no signicant difference (F(1,46) =
2.218, p = 0.143). For specic time points, the proportion of
negative tests for olanzapine and placebo groups respectively
were 0.83 (N = 23) and 0.64 (N = 22) at baseline, 0.86
(N = 7) and 0.75 (N = 8) at the end of treatment (week
16), and 0.71 (N = 7) and 0.73 (N = 11) at the follow-up
visit (week 20). The proportions of subjects who maintained
negative drug screens throughout the treatment period in the
olanzapine group (47.8%, N = 23) and the placebo group
(36.0%, N = 25) showed no signicant difference (
2
(1,
N = 48) = 0.289, p = 0.591).
Repeated Measures Analyses
Table 2 shows the signicant results fromthe 23 repeated-
measures ANOVAs conducted on the change scores of
the Craving Questionnaire, the Barnes Akathisia Scale, the
Simpson-Angus Scale, the AIMS, and the seven ASI subscales
at baseline (visit 1), end of treatment (visit 16), and follow-up
(visit 17), to assess the effect of the group (olanzapine versus
placebo; between-subjects effects) over time (within-subjects
effects). Although there were signicant within-subjects (time)
effects for the Craving Questionnaire, the AIMS, and the ASI
employment, family, alcohol, and drug subscales, there were
no signicant differences between the olanzapine and placebo
groups on any of the measures.
Adherence and Side Effects
In the olanzapine group, the amount of olanzapine received
by each participant ranged from 2.5 to 20 mg/day, with a mean
of 6.8 and a median of 5.0 mg/day. As determined by pill count,
50 Olanzapine in Cocaine Dependence JanuaryFebruary 2009
TABLE 2. Repeated measures ANOVA on change scores

Signicant differences on pairwise

Variable Effect F df p
2
analyses (p < 0.05)

Craving Questionnaire Time 33.919 2,30 <0.001 0.693 B vs. E, B vs. F

AIMS Time 6.529 2,30 <0.01 0.303 B vs. F, E vs. F
ASI employment Time 13.900 2,26 <0.001 0.517 B vs. F (olanzapine group);
B vs. E, B vs. F (placebo group)

Group time 4.089 2,26 <0.05 0.239

ASI alcohol Time 9.248 2,26 <0.01 0.416 B vs. E, B vs. F
ASI drug Time 25.834 2,26 <0.001 0.665 B vs. E, B vs. F
ASI family Time 9.487 2,26 <0.01 0.422 B vs. E

Only signicant effects are reported. Degrees of freedom vary because of missing data. None of the measures showed a signicant main effect of group (ie,
olanzapine vs. placebo); only the ASI employment subscale showed a signicant effect of group time. The Barnes Akathisia Scale, the Simpson-Angus Scale,
and the ASI psychiatric, legal, and medical subscales showed no signicant effects of time, group, or group time.

B = baseline (week 1), E = end of treatment (week 16), F = follow-up (week 20).

Because both time and group time effects were signicant for this measure, the overall main effect was not interpreted. Instead, simple main effect analyses
were conducted separately for each group and showed a signicant effect of time for each; the signicant differences across time by pairwise analyses within each
group are shown.
the mean percent adherence to prescribed olanzapine (93.4%,
SD 9.9%) and prescribed placebo (90.1%, SD 13.1%) did not
signicantly differ by one-way ANOVA (F(1,43) = 0.896,
p = 0.349). Table 3 shows the percentage of participants in
the overall sample who reported experiencing each side effect
(at any time from visit 2 to visit 17), as well as the percentage
by treatment group assignment (olanzapine versus placebo).
Attrition
The numbers of sessions attended were 10.0 (mean; SD
5.7) and 10.0 (median) for the olanzapine group and 9.8
(mean; SD 6.2) and 8.0 (median) for the placebo group. To
address the issue of attrition, we divided the sample into two
groups: subjects who completed at least eight visits (ie, half)
during the treatment period (N = 28) versus those who had
fewer than eight total visits (N = 20). A one-way ANOVA
showed no signicant difference between the two groups with
regard to age (F(1,46) = 0.185, p = 0.669), and a chi-square
square analysis revealed no signicant difference with regard
to ethnicity (
2
(1, N = 48) = 0.000, p = 1.000). There
was also no signicant difference regarding group assignment
to olanzapine versus placebo (
2
(1, N=48) = 0.002, p =
0.961). We conducted a series of one-way ANOVAs to examine
potential baseline differences between these two groups on the
dependent measures. Results showed no signicant differences
with regard to scores on the Craving Questionnaire (F(1,46)
= 0.062, p = 0.805), the Barnes Akathisia Scale (F(1,45)
= 1.133, p = 0.293), the Simpson-Angus Scale, (F(1,45) =
0.288, p = 0.594), the AIMS (F(1,45) = 1.082, p = 0.304),
the ASI medical subscale (F(1,43) = 0.736, p = 0.396), the
ASI employment subscale (F(1,44) = 0.069, p = 0.794),
the ASI alcohol subscale (F(1,44) = 0.002, p = 0.966),
the ASI drug subscale (F(1,44) = 0.886, p = 0.352), the
ASI legal subscale (F(1,44) = 0.354, p = 0.555), the ASI
TABLE 3. Percentage of participants endorsing side effects (N =
45)

Total sample Olanzapine Placebo

Side effect (%) (%) (%)
Any side effect 97.8 100 95.7
Increased appetite 73.3 86.4 60.9
Weight gain 66.7 68.2 65.2
Somnolence 64.4 72.7 56.5
Dry mouth 55.6 68.2 43.5
Postural hypotension 37.8 50.0 26.1
Constipation 33.3 27.3 39.1
Akathisia 33.3 40.9 26.1
Muscle twitching 28.9 31.8 26.1
Non-aggressive
behavior changes
26.7 27.3 26.1
Neck rigidity 26.7 27.3 26.1
Asthenia 22.2 27.3 17.4
Dizziness 20.0 22.7 17.4
Tremor 20.0 18.2 21.7
Articulation
impairment
20.0 18.2 21.7
Stuttering 20.0 18.2 21.7
Abdominal pain 17.8 13.6 21.7
Chest pain 17.8 9.1 26.1
Tachycardia 15.6 9.1 21.7
Amnesia 13.3 22.7 4.3
Euphoria 13.3 13.6 13.0
Peripheral edema 6.7 9.1 4.3
Rash 6.7 9.1 4.3
Blepharitis 6.7 9.1 4.3

Excludes three subjects who attended only the baseline visit.

Hamilton et al. JanuaryFebruary 2009 51
family subscale (F(1,44) = 0.570, p = 0.454), and the ASI
psychiatric subscale (F(1,43) = 0.019, p = 0.891).
DISCUSSION
Despite a plausible theoretical rationale of dopamine
blockade (and possibly serotonin blockade) predicting efcacy
for olanzapine in cocaine dependence, we found no difference
between olanzapine and placebo on any outcome measure
in our study. Some secondary outcome measures showed
improvement over time, but these were equivalent between
the two treatment groups. Our negative results are consistent
with those of a previous controlled study of olanzapine.
11
They also mirror ndings with risperidone, another second-
generation antipsychotic, which reduced cocaine craving and
use somewhat in case reports
17,18
and an open-label trial
19
but
did no better than placebo in a controlled study.
20
Complaints of side effects were common in our study,
but those reported more often with olanzapine than placebo
were primarily common ones such as increased appetite,
somnolence, and dry mouth. Although subjects reported sub-
jective akathisia more often with olanzapine than with placebo,
objective assessment of akathisia and other extrapyramidal
effects did not differ signicantly between the two groups,
despite high medication adherence by pill count in both groups.
No unexpected or previously unreported side effects occurred.
Our study has limitations. The subjects were all male
veterans; thus, our results might not generalize to other
populations. However, in the only other controlled study of
olanzapine in cocaine dependence, Kampman and colleagues
found similarly negative results in a non-veteran population
that included both men and women.
11
A further limitation is
the power of our study, which was 0.591 (based upon a t test
for means), in part because of the somewhat high placebo
response. A sample size of 80 would be required to detect a
statistically signicant difference at the 0.05 level with power
of 0.591. The fact that a substantial number of our subjects
completed fewer than half of the treatment visits could be seen
as another limitation. However, we believe this reects the
usual clinical experience of treating cocaine dependence, and
the results for these subjects did not differ from the results of
subjects who completed half the number of treatment visits.
Likewise, although we cannot rule out the possibility that
longer treatment might have produced more positive results,
the 16 weeks of treatment in our study appears sufcient to
have demonstrated any clinically practical effectiveness.
In summary, given two negative controlled trials of olan-
zapine as well as a negative controlled trial of risperidone, it
appears that olanzapine, and probably other currently available
atypical antipsychotics, are not effective treatments for cocaine
dependence. Further progress in this area must await research
on other classes of medications.
Supported by an investigator-initiated grant from Eli Lilly
and Company, Indianapolis, Indiana.
The authors thank Francisco Aviles-Roig, MD, for pro-
viding patient care and data collection; Juliane Souchek,
PhD, and Ellen Teng, PhD, for statistical consultation; Soa
Simotas, PhD, Jo Daugherty Bailey, PhD, LMSW, Brenda
Schubert, and Dana Foster for research coordination; and
Phillip Colvard for data entry.
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52 Olanzapine in Cocaine Dependence JanuaryFebruary 2009